It is considered that autoimmune diseases are induced because lymphocytes that inherently do not have self-reactivity have acquired autoreactivity or because autoreactive lymphocytes have not been deleted completely in thymus and the like. Of such diseases, rheumatoid arthritis (RA) is considered to be induced by immunoreaction of lymphocytes (particularly T cells and B cells) for type II collagen mostly present in one's own joints. It is a serious disease that accompanies infiltration of T cells and B cells into the joint part, activation and proliferation of these cells in the joint part, and with progression of symptoms, abnormal proliferation of synovial cells in the joint to result in destruction of the joint. In addition, because a great number of activated lymphocytes infiltrate into the joint tissues of RA patients, the activated lymphocytes are considered to play an important role in the establishment or progress of the disease state of RA.
It is generally known that, when lymphocytes are activated by an antigen, type 1 helper T cell (Th1 cell) in the lymphocytes produces cytokines, such as interleukin 2 (IL-2), interferon-γ (IFNγ) and the like, and the produced IL-2 and IFN-γ cause proliferation and differentiation of lymphocytes, particularly T cell. Because the IL-2 level is extremely low despite the presence of a great number of activated lymphocytes in the joint tissues of RA patients, the presence of a lymphocyte growth factor other than IL-2 has been predicted [Journal of Experimental Medicine, vol. 168, p. 1573 (1988)].
In recent years, interleukin 15 (IL-15) has been cloned as a new cytokine that promotes proliferation and differentiation of lymphocytes (T and B cell) [Science, vol. 264, p. 965, (1994)]. It has been clarified that IL-15 receptor consists of a chain specific to IL-15, β chain common to IL-15 and IL-2, and γ chain common to IL-15, IL-2, IL-4, IL-7, IL-9 and IL-13 receptors [EMBO Journal, vol. 13, p. 2822 (1994); EMBO Journal, vol. 14, p. 3654 (1995)]. It was also elucidated that a signal transduction pathway via tyrosine kinase, represented by JAK1 and JAK3, is present in the downstream of β chain and γ chain [Science, vol. 266, p. 1782 (1994)]. Therefore, it is expected that the pharmacological activity induced by the binding of IL-15 and IL-15 receptors should be the promotion of the proliferation of lymphocyte, which is of the same kind as that provided by the binding of IL-2 and IL-2 receptor. The IL-2 and IL-9 producing cell is T cell, particularly helper T cell activated by antigen, whereas the IL-7 producing cell is mainly stroma cell. The IL-15 producing cell has been reported to be macrophage, dendritic cell, synovial cell and the like [Science, vol. 264, p. 965 (1994)]. The presence of IL-15 at an extremely high concentration in the synovial fluid of RA patients has been recently reported, thereby suggesting the important role of IL-15 as a growth factor for the growth of activated lymphocytes in the joint part of RA. Furthermore, IL-15 has been reported to have many activities to promote migration of T cell into inflammatory sites, to activate memory T cell, promote production of inflammatory cytokines such as tumor necrosis factor (TNF)-α etc., and the like, besides the promotion of the proliferation of activated lymphocyte [Nature medicine, vol. 3, p. 189 (1997)], and its important role in the onset and the progress of various autoimmune diseases such as Crohn's disease, lupus nephritis in systemic lupus erythematosus and the like has been increasingly clarified.
From the foregoing, inhibition of the proliferation of IL-15-dependent activated lymphocyte is considered to be particularly effective for the improvement of the symptoms of autoimmune diseases represented by RA.
As conventional therapeutic agents of autoimmune diseases, particularly RA, pharmaceutical agents such as gold preparation, penicillamine, bucillamine, azathioprine, cyclophosphamide, methotrexate and the like have been widely used. These have an effect of inhibition of the proliferation of synovial cells in joints, but also have an antagonistic and inhibitory action on the metabolism of nucleic acid. As a result, a long-term dose thereof causes manifestation of side effects such as dyshematopoiesis, digestive disturbance and the like at high frequency, and is also associated with problems such as easy infection and the like. Accordingly, they are not therapeutically satisfactory. In addition, while adrenocorticosteroid is effective for these diseases, the use of this agent is associated with the expression of grave side effects such as moon face, degradation of adrenal gland function, avascular necrosis of the femoral head, and the like. It has been reported that, while leflunomide approved in the US as an antirheumatic drug shows a superior therapeutic effect, it shows a long half-life in blood and causes side effects of digestive disturbance, liver impairment, rash and the like [The Lancet, vol. 353, pp. 259-266 (1999)], and a clinically superior therapeutic agent is desired.
Thus, the need for a therapeutic agent for autoimmune diseases such as RA and the like, which has a superior treatment effect as compared to conventional pharmaceutical agents, and which is associated with less side effects is considered to be extremely high.
As mentioned above, the proliferation of activated lymphocytes in joint tissues is deeply involved in the progress of arthritis in RA, and the involvement of IL-15 in the proliferation of activated lymphocyte has been suggested. Thus, a compound that inhibits signal transduction from IL-15 receptors (β, γ chain commonly found in IL-2, and γ chain commonly found in IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15) via tyrosine kinase is expected to show a superior effect for the prophylaxis or treatment of autoimmune diseases such as rheumatoid arthritis and the like. Moreover, a compound that inhibits, besides the aforementioned action, production of IL-15 itself or production of inflammatory cytokines induced by IL-15, such as TNF-α and the like, is considered to show a more superior effect in the prophylaxis or treatment of autoimmune diseases such as rheumatoid arthritis and the like. However, there has been no report so far on the study of a compound having inhibitory effects on the proliferation of activated lymphocyte as a therapeutic agent of autoimmune diseases or a therapeutic agent of RA, taking note of IL-15.
Journal of Medicinal Chemistry, vol. 21, pp. 1178-1181 (1978) discloses 1-hydroxynaphthamide derivative as an anthelmintic, and Journal of Medicinal Chemistry, vol. 20, pp. 826-829 (1977) and WO 94/05649 disclose a salicylamide derivative and a hydroxycoumarin derivative as antibacterial agent, respectively. In addition, WO 99/41239 discloses quinoline or indole derivative as a B cell inhibitor. However, inhibitory effects on the proliferation of activated lymphocyte of these compounds taking note of IL-15 have not been disclosed at all.
The present inventors have intensively studied in view of the above-mentioned situation, and as a result, found that a fused bicyclic amide compound represented by the following formula and pharmaceutically acceptable salts thereof inhibit a cytokine response that induces proliferation, differentiation and the like of various immunocompetent cells such as lymphocytes (T cell, B cell), macrophage and the like, due to the addition of cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15 and the like, in the presence or absence of antigen or mitogen. Particularly, they have found that the compound and the salt inhibit IL-15-dependent proliferation of activated lymphocytes and production of inflammatory cytokines induced by IL-15, or IL-1, IL-6, IL-12, IL-15, IL-18, TNF-α and the like, which resulted in the completion of the present invention.